According to the Central Brain Tumor Registry of the United States (CBTRUS), as of March 2012, brain and central nervous system (CNS) tumors are the second leading cause of cancer-related deaths in children under age 20 and in males ages 20-39. Brain and CNS tumors represent the fifth leading cause of cancer-related deaths in females ages 20-39. According to 2010 statistics, more than 688,000 people were living with primary CNS tumors in the United States (Porter et al., Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology, Neuro. Oncol. 12:520-27 (2010)). Of those tumors, 138,000 were malignant tumors and 550,000 were nonmalignant tumors. CBTRUS estimated 69,720 new cases of primary brain tumors in 2013.
Treatment options for brain tumors include surgery, radiation therapy, and chemotherapy. The recommended therapy depends on several factors, such as size and type of tumor, whether the tumor is affecting any vital parts of the brain, and whether the tumor has metastasized to other parts of the CNS or the body.
One of the challenges to treating primary brain tumors with chemotherapeutic agents is the existence of unique physical features in the brain which prevent most therapeutic agents from accessing tumor tissue. First, the blood-brain barrier (BBB) restricts the passage of most endogenous and exogenous substrates from traversing the brain parenchyma. Brain endothelium cells differ from those in other organs. In other organs, intracellular clefts are found in the capillary beds and fenestrae are formed by the endothelial cells, which aid in diffusion of substrates into and across the endothelial cells. Brain endothelial cells have continuous tight junctions, an absence of fenestrations, and very low pinocytic activity. A basal membrane and extracellular matrix surround brain endothelial cells. Permeability is mainly controlled by astrocytic and pericytic foot processes covering most of the endothelial cell surface. Permeability is modulated by chemical factors and signals released by astroglia. Further, unique protein composition (including high expression of occluding proteins) creates high electrical resistance in brain capillaries, which forms a barrier against polar and ionic substances. Collectively, these features form a BBB that protects the brain, but which also prevents most therapeutic agents from entering the brain.
In the case of primary brain tumors, the blood-tumor barrier (BTB) provides a further challenge to delivering therapeutic agents to malignant tissue. In primary tumors such as gliomas, the BTB may be variably disrupted in the tumor and surrounding tissue. Portions of tumors with a mainly intact BTB may be shielded from chemotherapy, greatly complicating the ability to therapeutically treat such tumors.
Despite advances in treatment modalities for primary brain tumors, the overall prognosis remains poor. Given the increasing prevalence, the poor prognosis, and the lack of effective treatment options, a substantial need exists for the development of agents for treating primary brain tumors.